Novel 18, 20beta-dioxygenated-5beta-pregnanes



United States Patent "Ice 3,275,620 NOVEL18,20B-DIOXYGENATED-Sfl-PREGNANES Georges Muller, Nogent-sur-Marne,France, assignor, by mesne assignments, to Roussel-UCLAF, S.A., Paris,France, a corporation of France No Drawing. Filed June 27, 1%0, Ser. No.38,723 Claims priority, application France, June 29, 1959,

1 Claim. 01. zen-239.55

The invention relates to novel 18,20-dioxygenated steroids. It relatesespecially to 18,20fl-dioxygenated B- pregnanes, of the formula:

CH3 Groom O I \0 R3 011 wherein R is a member selected from the groupconsisting of H H :0, and 0H ooo-orr,

and R and R are members selected from the group consisting of H andCO-CH and more particularly to 304, 1 8,2OB-triacetoxy-SB-pregnane- 1l-one, Sfi-pregnane-18,20fi-diol-3,1l-dione and18,20/3-diacetoxy-5,8-pregnane-3,1l-dione.

Jeger et al. (Helv. Chem. Acta, 1959, Vol. 42, page 1124) has recentlydescribed an attack on the C position by an oxygenated function in the C5 position activated by lead tetraacetate. By this method, an etherfunction between the C position and the C 6 position was obtained, theopening of the oxygenated bridge being thereafter achieved in thefollowing stage of the synthesis. The reactions made up to this timeinvolved the use of starting materials of extremely simple structureonly, which compounds have been devoid of substituted functional groups.It would be impossible to predict what the results would be startingwith the steroids intermediate in the synthesis of cortisone compoundsand especially those having a ketone functions in the C position as Wellas the natural orientation in C position (55).

It is an object of this invention to obtain18,20f3-dioxygenated-Sfi-pregnanes of the formula OR; Q

wherein R is a member selected from the group consisting of :0, and 0110-o o-orr,

and R and R are members selected from the group consisting of H andCO-CH It is a further object of this invention to develop a 3,275,620Patented Sept. 27, 1966 process of producing novell8,2OB-dioxygenated-SB-pregnames.

A still further object of this invention is the production of theintermediate l8,20,8-oxido-5 8-pregnane-3,ll-dione.

These and other objects of this invention will become more apparent asthe description thereof proceeds.

I have found that the classic methods of opening the etheric analogs oftetrahydrofuran and more particularly the method of using zinc chloridein acetic acid anhydride, can be used to produce 18,20fidioxygenated-SB-pregnanes of the formula CH CHgORz on I i ORa C 3 whereR R and R have the values assigned above starting withl8,20,8-oxido-5B-pregnane-3a-ol-11-one and its acetate. These startingmaterials for the invention may be prepared by oxidizing the3-monoacetate of 5ppregnane-3a,2OB-diol-1l-one by lead tetraacetatewhile heating to reflux in benzene, pouring the reaction mixture in anaqueous solution of sodium iodide, adding to the mixture sodiumhyposulfite until the mixture is decolorized, isolating the rawoxidation product and purifying this last by chromatography on alumina.The 3a-acetoxy- 18,20fl-oxido-5B-pregnane-ll-one thus obtained is thensaponified into 18,20/3-oxido-5 B-pregnane 3ot-ol-l1-one by alcoholicsodium hydroxide.

The products of the invention are valuable intermediates in thesynthesis of physiologically active products having an oxygenatedfunction in the C position of the steroid molecule such as, for example,altlosterone. The stages of one such synthesis producing the 18-11lactone of o -pregnene-llfi-ol-3,20-dione-l8-oic: acid, a precursor ofaldosterone are shown in Table I. The synthesis steps are classic insteroid chemistry and well known to those skilled in the art.

Chromic acid anhydritllfi/in acetic acid The process for the productionof the products of the invention consists essentially of treating an18,20;8-oxidowith zinc chloride in acetic acid anhydride at about roomtemperature, isolating the product formed thereby and treating thelatter with an alkaline reagent such as refluxing with an alkali metalhydroxide in a lower alkanol, for example with potassium hydroxide inethanol. An 18,20/3-dioxygenated-Sfi-pregnane-11-one is obtained of theformula on, ornoH E wherein R is or This latter product is acetylatedaccording to classic methods such as heating with acetic acid anhydridein the presence of a tertiary organic base such as pyridine to obtainthe diacetoxylated compound or the corresponding triacetoxylatedcompound. Table II is a schematic flow diagram of the reactions of theinvention.

4 Table II AGO-- CHROH CHzOAc l 3 OAc III v 1-1 H 0112011 CH OAO I A 0-UAOH =f U 0A6 VI VII H i AC=*-CGH3 The 18,208-oxido-5fi-pregnane-3,1l-dione serving as an intermediate in thepreparation of the compounds of the invention is obtained by oxidationof 18,20,8-oxido-55- pregnane-3a-ol-11-one according to known processessuch as chromic acid in an aqueous acidic media, preferably chromic acidin concentrated sulfuric acid, at temperatures below room temperature.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments. The melting points are instantaneous meltingpoints determined on a Kofler block.

EXAMPLE I Preparation of 3a-acet0xy-1 8,20/3-0xid0- 5 ,B-pregnane-l I-one 5 grams of the 3-monoacetate of 5fi-pregnane-3a,20fldiol-ll-one,M.P. 204 C. were introduced into 200 cc. of benzene. 10 cc. of solventwere distilled off, 10 grams of lead tetraacetate were added and themixture was refluxed for 16 hours. It was poured into 200 cc. of Watercontaining grams of sodium iodide and solid sodium hyposulfite was addeduntil the mixture was decolorized. The mixture was decanted andextracted with ether. The ether extracts were separated, combined,washed with water, with sodium bicarbonate, dried over magnesium sulfateand evaporated to dryness under vacuum. 6 grams of a resin wererecovered which were chromatographed on 150 grams of neutral alumina.Elution was effected with petroleum ether containing 2% of methylenechloride. There was obtained 3.31 grams of a resin which oncrystallization from petroleum ether furnished 1.42 grams of 3a-acetoxy-l 8,205-oxido-5fi-pregnane-l l-one, having a melting point of168 C. and a specific rotation [a] =+67i5 (CHCl The product which hasnot yet been described is present in the form of small, colorlesscrystals, insoluble in water, soluble in alcohol, ether, acetone,benzene and chloroform, poorly soluble in petroleum ether.

Analysis.-C H O molecular weight=374.50. Calculated: C, percent, 73.76;H, percent, 9.15; 0, percent, 17.09. Found: C, percent, 73.8; H,percent, 9.2; 0, percent, 17.5.

EXAMPLE 11 Production of SB- regnane-SaJ8,20,8-triol-1l-onc (II) 25 mgm.of zinc chloride were dissolved in 0.5 cc. of acetic acid anhydride byheating and the solution was then cooled to C., 100 mgm. of the acetateof 18,205- oxido-5fi-pregnane-3et-ol-ll-one (I) obtained by the processof Example I was added thereto, and the mixture was allowed to stand foran hour at 20 C. The reaction mixture was poured over ice, left incontact with the ice for an hour and then extracted with methylenechloride. The combined extracts were washed with water, with sodiumbicarbonate, dried over magnesium sulfate and evaporated to dryness invacuo. The resin thus obtained was dissolved in 2 cc. of 1N alcoholicpotassium hydroxide. The solution was refluxed for one hour, 20 cc. ofwater and ice were added thereto and the solution was extracted withmethylene chloride. The combined extracts were washed with water, driedover magnesium sulfate and evaporated to dryness in vacuo. The residuewas crystallized from ether to obtain 30 mgm. of 5fl-pregnane-3u,l8,ZOfi-triol-ll-one having a melting point of 218 C. The product isobtained in the form of small colorless platelets, insoluble in waterand benzene, slightly soluble in ether and ethyl acetate, soluble inmethanol and ethanol. It has not yet been described in the literature.

EXAMPLE III Production of 3u,18,20fi-triacetoxy-5flpregnane-Il-one (III)0.1 gm. of 5fl-pregnane-3a,18,20B-triol-1l-one, obtained according tothe preceding example, was heated to 55 C. for 30 minutes in 0.5 cc. ofpyridine in the presence of 0.3 cc. of acetic acid anhydride. Themixture was cooled to 20 C., 5 cc. of water were added and the mixturewas vacuum filtered. The filter cake was washed with water and dried at100 C. to obtain 0.125 gm. (92% of theory) of3a,18,ZOfi-triacetoxy-Sfi-pregnane-1l-one (HI), having a melting pointof 153 C. The product is obtained in the form of small colorless prisms,insoluble in water and petroleum ether, soluble in methylene chloride.This product is novel.

EXAMPLE IV Production of 18,2QB-OxidO-iB- regnan12-3,]1-dione (V) 1.19gm. of 18,20,8-oxido-5,B-pregnane-3a-ol-ll-one (IV), obtained bysaponifying the 3a-acetoxy-18,20,B-

oxido-SB-pregnane-ll-one (I) of Example I Were dissolved in 15 cc. ofacetone, the solution was iced and 2.07 cc. of a solution of 25 gm. ofchromic acid and 37 gm. of concentrated sulfuric acid in 40 cc. of waterwere added at a temperature between 5 and 1 C. The mixture was agitatedfor 35 minutes and 1 cc. methanol was added. The mixture was agitatedagain for 5 minutes, poured into water and vacuum filtered. The filtercake was washed with water and dried at 90 C. 1.1 gm. (95% of theory) of18,20f3-oxido-5fi-pregnane-3,ll-dione, V, having a melting point of 176C. and a specific rotation [oz] =-+57iZ (c.=0.5% in chloroform), wasobtained.

This product, which is novel, is obtained in the form of small colorlesscrystals, insoluble in water, slightly soluble in ether, soluble inacetone and chloroform.

EXAMPLE V Production of 5B-pregnane-18,20{3-di0l- 3,1l-di0nc (VI) 1.2gm. of 18,ZOB-oxido-Sti-pregnane-Fa,11-dione, obtained according to thepreceding example, was treated according to the process indicated inExample II and 5,8- pregnane-l8,20B-diol-3,1l-dione was obtained with ayield of 30%. This product, which has not yet been described, isobtained in the form of small colorless crystals, insoluble in water,slightly soluble in ether, soluble in chloroform and having a meltingpoint of 204 C.

EXAMPLE VI Production of I8,20fi-diacet0xy-5fl-pregnane- 3,1J-dione(VII) 0.2 gm. of -pregnane-18,20fi-diol-3,11-dione (VI), obtainedaccording to the preceding example were heated to 60 C. for 30 minutesin 1 cc. of pyridine in the presence of 0.7 cc. of acetic acidanhydride. The mixture was cooled to 20 C., 10 cc. of water are addedthereto and it was vacuum filtered. The filter cake was washed withWater and dried at C. 0.260 gm. of theory) of18,20fi-diacetoxy-5fi-pregnane-3,1l-dione, VII, were obtained. Theproduct is novel.

Various modifications of the process may be made without departing fromthe spirit or scope thereof, and it is to be understood that theinvention be limited only as defined in the appended claim.

I claim:

A compound having the formula References Cited by the Examiner Fieser etal., Natural Products Related to Phenanthrene (third edition) (1949),pp. 428, 220, 232 and 451.

Heusler et a1., Experientia 16, 21--24 (January 1960).

LEWIS GOTTS, Primary Examiner.

LESLIE H. GASTON, MORRIS LIEBMAN, Examiners.

M. L. WILLIAMS, H. FRENCH, Assistant Examiners.

